With the increasing attention to the role of magnesium in health, think of taking supplements to prevent fatigue or muscle cramps, it is important that we understand how magnesium levels are regulated within the body.
Magnesium (Mg2+) is a mineral that is crucial in many physiological processes, such as muscle contraction and blood pressure regulation. Mg2+ homeostasis is regulated by absorption in the intestine, storage in bone, and reabsorption from the pro-urine in the kidney. Within the kidney, the protein Cyclin M2 (CNNM2) is one of the key players in Mg2+ reabsorption. Pathogenic mutations in this gene are associated with decreased serum Mg2+ levels, called hypomagnesaemia, and excessive urinary Mg2+ wasting. Moreover, recessive mutations are linked to structural brain defects, such as myelinisation abnormalities. Yet, the role of CNNM2 in physiology has not been identified.
In our study, we employed several Cnnm2 knock out mouse models to investigate the role of CNNM2 in Mg2+ homeostasis. The cruciality of CNNM2 during embryonic development became evident, as approximately 30% of embryos demonstrated exencephaly. The few pups that were born alive, survived for less than 8 hours and showed decreased serum Mg2+ levels and increased calcium (Ca2+) levels. Adult mice heterozygous for Cnnm2 also showed decreased serum Mg2+ levels and increased Ca2+ compared to wild type littermates, independent of being fed with deficient or saturated Mg2+ diets. The kidneys were not able to compensate for the decreased serum Mg2+ levels and, interestingly, the faeces contained higher amounts of Mg2+.
In conclusion, CNNM2 is vital for embryonic development and Mg2+ homeostasis. Our data suggest a previously undescribed role of CNNM2 in the intestine, which may contribute to the Mg2+ deficiency in mice and patients. This also emphasises that congenital and acquired Mg2+ deficiencies, due to medications, might not only have a renal component, but also that the intestines play a role in the pathogenesis of hypomagnesaemia.
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